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• W2164449595 abstract "To the Editor: Chagas disease, caused by the parasite Trypanosoma cruzi, affects 10 to 12 million people each year in Latin America, with Bolivia having the highest prevalence of infection (see “Outlook: Chagas disease”1Outlook Chagas disease.Nature. 2010; 465: S3-S22PubMed Google Scholar and references therein). In the chronic phase, Chagas infection may present as an indeterminate form in which 60% of infected individuals remain asymptomatic despite having positive serologic reactions for T cruzi. In the remaining 40% of patients with Chagas disease, tissue inflammation leads to organ damage, affecting the cardiac, digestive, or nervous systems up to 25 years after initial infection. Several studies identified genetic markers for disease establishment and progression in Venezuelans, Brazilians, Peruvians, Colombians, and Mexicans,2Cunha-Neto E. Nogueira L.G. Teixeira P.C. Ramasawmy R. Drigo S.A. Goldberg A.C. et al.Immunological and non-immunological effects of cytokines and chemokines in the pathogenesis of chronic Chagas disease cardiomyopathy.Mem Inst Oswaldo Cruz. 2009; 104: 252-258Crossref PubMed Scopus (81) Google Scholar but no genetic studies have been conducted previously in Bolivians. Cytokines produced in response to T cruzi infection appear to modulate disease progression by enhancing or inhibiting parasite replication in a variety of cell types. In particular, the TH2 cytokine IL-4 maintains inflammation and parasite persistence in Chagas disease,3Ribeiro B.M. Crema E. Rodrigues Jr., V. Analysis of the cellular immune response in patients with the digestive and indeterminate forms of Chagas’ disease.Hum Immunol. 2008; 69: 484-489Crossref PubMed Scopus (19) Google Scholar whereas TH1 cytokines maintain control of parasitism4Reed S.G. In vivo administration of recombinant IFN-gamma induces macrophage activation, and prevents acute disease, immune suppression, and death in experimental Trypanosoma cruzi infections.J Immunol. 1988; 140: 4342-4347PubMed Google Scholar but can also contribute to the development of chronic myocarditis.5Gomes J.A. Bahia-Oliveira L.M. Rocha M.O. Martins-Filho O.A. Gazzinelli G. Correa-Oliveira R. Evidence that development of severe cardiomyopathy in human Chagas’ disease is due to a Th1-specific immune response.Infect Immun. 2003; 71: 1185-1193Crossref PubMed Scopus (234) Google Scholar To determine whether genetic variation at the IL4 gene is associated with T cruzi infection in Bolivians, we performed a resequencing study of an approximately 12-kb region around the IL4 locus, including 470 base pairs (bp) of coding (exon) sequence, 368 bp of 5′ untranslated region, 82 bp of 3′ untranslated region, and 11,453 bp of intronic sequence. The study included 110 individuals from the Department of Cochabamba, Bolivia, with infection status serologically confirmed by 2 different diagnostic tests (HAI Chagas Polychaco; Laboratorio Lemos, S.R.L., Buenos Aires, Argentina, and IFI Biocientifica S.A., Buenos Aires, Argentina). Each subject was classified according to the serologic results as a case (positive serology) or a control (negative serology). Our sample included 74 infected subjects (mean age, 49 years; range, 18-83 years; 47 female and 27 male) and 36 controls (mean age, 45 years; range, 18-73 years; 18 male and 18 female). DNA from 1 chimpanzee was used to infer the ancestral state at each polymorphic position. We identified a total of 45 polymorphic sites (Table I); all polymorphisms were in Hardy-Weinberg equilibrium. Only 3 variants were located in the coding region: 2 previously reported silent changes (Leu15Leu in exon 1 and Asp111Asp in exon 3) and 1 novel amino acid replacement (Leu120Ser in exon 3). All 3 coding variants were observed only in infected subjects. Sixteen variants (including the 3 exonic single nucleotide polymorphisms [SNPs]) were singletons, and all 16 occurred only in the infected subjects. Two singletons were present in 1 individual; therefore, 15 of 148 chromosomes from infected subjects and none of the 72 control chromosomes carried singletons (Fisher exact test, P = .0066). The fact that all 16 singletons were confined to the group of infected subjects is striking and suggests that rare alleles may contribute to altered IL4 expression and/or function and ultimately to disease susceptibility. Overall, 19 of the 45 polymorphisms (including 14 of the 16 singletons) are newly reported. Of the remaining variants with available frequency information (23 of 26), 20 have been previously reported in both African Americans and Europeans, 1 in African Americans only, 1 in Europeans only, and 1 in Asians only (Database of Single Nucleotide Polymorphisms [dbSNP], accessed July 2010). Chromatogram sequence traces of the 12 novel singletons not confirmed by multiple sequence reads are shown in this article’s Fig E1 in the Online Repository at www.jacionline.org.Table IPolymorphisms in the IL4 gene present in 110 BoliviansLocationSNP positionrs numberAllelesAncestral/derivedDAFAlternate namePromoter/5′ region10889rs71645903C/G<0.0110905rs71645904G/A0.1910926rs71645905A/G<0.0110957rs10065221A/G0.0210960rs10058157T/C0.0211781rs71645906C/T<0.0111903rs2243250C/T0.54−590 C/T12348rs17772853C/T0.02Exon 112459rs2070874C/T0.53+33 C/T12536rs2243251A/G<0.01Leu15LeuIntron 213172rs71645907C/G<0.0113239rs71645908C/T<0.0113322rs71645909A/G<0.0113475rs734244C/T0.5913571rs71645910C/T<0.0113575rs71645911G/A0.0115508rs2227284T/G0.5015962rs2227282C/G0.5316082rs2243263G/C0.4816510rs71645912G/C0.0316669rs2243267G/C0.5216717rs71645913C/T<0.0116746rs2243268A/C0.5116783rs9282745T/A<0.0116892rs2243270G/A0.6617036rs2243308C/T0.0117477rs71645914C/A<0.0117615rs2243274A/G0.49Exon 318338rs35648164C/T0.01Asp111Asp18364rs71645915T/C<0.01Leu120SerIntron 318383rs71645916C/A<0.0119058∗The ancestral state of the 70 bp repeat (1 copy) is rare in human beings (0.01 in Bolivians); the frequency of the minor (3 copy) allele is shown instead.1/2 or 30.4970 bp repeat19108rs71645917T/C0.0619118rs71645918G/A<0.0119178rs2243281T/C0.1419376rs2243283C/G0.0619464rs71645919C/G<0.0119775rs2243284G/A0.5019776rs2243285G/T0.1720388rs71645920A/T0.0120727rs2243288A/G0.5920915rs2243289A/G0.5320952rs2243290C/A0.563′ Region21659rs71645921A/G<0.0121766rs2243291C/G0.4822574rs2243293A/G0.6922590rs2243294G/A0.31DAF, Derived allele frequency.The −590 C/T SNP is shown in boldface. SNP position is in reference to AF395008 in GenBank.∗ The ancestral state of the 70 bp repeat (1 copy) is rare in human beings (0.01 in Bolivians); the frequency of the minor (3 copy) allele is shown instead. Open table in a new tab DAF, Derived allele frequency. The −590 C/T SNP is shown in boldface. SNP position is in reference to AF395008 in GenBank. Polymorphism levels, as summarized by nucleotide diversity (π) and the Watterson estimator of the population mutation rate parameter θ (θW), are unremarkable and similar to genome-wide averages in both the infected subjects (π = 0.00079 and θW = 0.00069) and uninfected controls (π = 0.00068 and θW = 0.00018). The Tajima's D (TD) statistic, summarizing information on the allele frequency spectrum, is expected to be near 0 under the neutral equilibrium model. A positive value indicates an excess of intermediate frequency variants, whereas a negative value indicates a skew toward rare variants. TD values in infected subjects and uninfected controls were compared with an empirical distribution of TD values in 318 genes resequenced in 24 African Americans and 23 Europeans (University of Washington–Fred Hutchinson Cancer Research Center Variation Discovery Resource, or Seattle SNPs). The TD value in infected subjects (0.46) falls in the top 7% and 42% of TD values, but TD in controls (1.78) falls in the top 2% and 5% of TD values among African Americans and Europeans, respectively, suggesting an excess of intermediate frequency variants in controls. The IL4 gene is characterized by strong linkage disequilibrium in populations of European, Asian, and African descent, and a correspondingly strong haplotype structure. In Asian and European HapMap samples, each population has 2 major haplotype classes that are tagged by a SNP located in the promoter region (−590C/T; rs2243250), which has been associated with increased gene transcription and elevated total serum IgE levels in subjects with asthma and atopy6Kabesch M. Tzotcheva I. Carr D. Hofler C. Weiland S.K. Fritzsch C. et al.A complete screening of the IL4 gene: novel polymorphisms and their association with asthma and IgE in childhood.J Allergy Clin Immunol. 2003; 112: 893-898Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 7Rosenwasser L.J. Klemm D.J. Dresback J.K. Inamura H. Mascali J.J. Klinnert M. et al.Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy.Clin Exp Allergy. 1995; 25 (discussion 95-6): 74-78Crossref PubMed Google Scholar as well as malaria.8Verra F. Luoni G. Calissano C. Troye-Blomberg M. Perlmann P. Perlmann H. et al.IL4-589C/T polymorphism and IgE levels in severe malaria.Acta Trop. 2004; 90: 205-209Crossref PubMed Scopus (31) Google Scholar Curiously, the frequencies of the haplotype classes are essentially reversed in European and non-European HapMap (Phase I) samples, in which the derived −590T allele at SNP rs2243250 occurs at 16% frequency in Europeans, 75% in Asians (Chinese and Japanese combined), and 83% in Africans (Yorubans). The frequency of the −590T allele is 54% in the Bolivian sample (Table I), intermediate to the frequency in the HapMap samples. Because of the unusual haplotype structure in worldwide samples and the functional role associated with the −590C/T SNP,7Rosenwasser L.J. Klemm D.J. Dresback J.K. Inamura H. Mascali J.J. Klinnert M. et al.Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy.Clin Exp Allergy. 1995; 25 (discussion 95-6): 74-78Crossref PubMed Google Scholar we stratified the haplotypes present in the Bolivians based on this SNP and refer to the 2 classes of haplotypes as clade A (defined by the derived T allele) and clade B (defined by the ancestral C allele) (Fig 1; rs2243250, position 11903). A visual representation of haplotypes at the IL4 locus is shown in Fig 1. In Bolivians, 49% of chromosomes from infected subjects and 64% of chromosomes from uninfected controls belong to clade A (Fisher exact test, P = .033; odds ratio, 0.54; 95% CI, 0.3001-0.9554). The ancient estimated age of divergence for clade A from clade B (40,000 years ago; range, 25,204-48,469; see the text of this article’s Online Repository at www.jacionline.org for details) places the split before the spread of modern human beings into the new world. Clade A haplotypes form a relatively homogeneous group in which nearly all observed haplotypes differ by only 1 or 2 SNPs from the common form despite the ancient estimate of divergence. Clade B haplotypes, on the other hand, are more heterogeneous and more divergent from each other (Fig 1; see this article’s Fig E2 in the Online Repository at www.jacionline.org). The combined observations of a relatively homogeneous group of haplotypes in the T cruzi–noninfected controls and a significant skew in the frequency spectrum toward intermediate frequency alleles in these individuals suggest that 1 or more variants on clade A haplotypes provide protection against T cruzi infection and, as a result, natural selection has favored the maintenance of these haplotypes in the Bolivian population. The selected SNP could be the functional −590C/T SNP or any other SNP that is in strong linkage disequilibrium with −590C/T. Alleles or haplotypes associated with increased expression of the IL4 gene, and a correspondingly stronger TH2 immune response, could provide a substrate for natural selection. For example, approximately 20% of T cruzi–affected individuals ultimately develop the cardiac form of Chagas disease, which can result in heart failure. A study of IL-10 and IFN-γ responses in 111 individuals with either the indeterminate or the cardiac form of Chagas disease revealed that high levels of IFN-γ and low levels of IL-10 are associated with heart damage, with the highest levels of IFN-γ corresponding to the most severe heart pathologies.5Gomes J.A. Bahia-Oliveira L.M. Rocha M.O. Martins-Filho O.A. Gazzinelli G. Correa-Oliveira R. Evidence that development of severe cardiomyopathy in human Chagas’ disease is due to a Th1-specific immune response.Infect Immun. 2003; 71: 1185-1193Crossref PubMed Scopus (234) Google Scholar These results suggest that a strong TH1 response, although important in limiting parasite replication during the acute phase,4Reed S.G. In vivo administration of recombinant IFN-gamma induces macrophage activation, and prevents acute disease, immune suppression, and death in experimental Trypanosoma cruzi infections.J Immunol. 1988; 140: 4342-4347PubMed Google Scholar can contribute to severe heart disease in the chronic phase. Consequently, during the indeterminate phase of infection, IL-4–producing T cells may be advantageous by balancing parasitism and tissue integrity, although this idea is at odds with studies showing a protective role for TH1 cytokine responses (and a counterproductive role for TH2 responses) with regard to control of parasite infection. Unfortunately, we do not have information other than T cruzi infection status for the individuals in our study, so we cannot make predictions about outcomes on the basis of IL4 genotype or directly address these seemingly paradoxical findings. However, it would not be surprising if the balance between TH1/TH2/T regulatory cytokines has different (opposing) influences on the likelihood of infection with T cruzi and on the subsequent morbidity associated with Chagas disease. Our study is the first to characterize variation in the IL4 gene in Bolivians and to examine genetic associations between IL4 and T cruzi infection in any population. We selected this gene for our study because of the key role TH2 cytokines play in the immune response to intracellular pathogens, such as T cruzi, and because a promoter polymorphism (C−590T; rs2243250) in this gene has been associated with differences in expression level7Rosenwasser L.J. Klemm D.J. Dresback J.K. Inamura H. Mascali J.J. Klinnert M. et al.Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy.Clin Exp Allergy. 1995; 25 (discussion 95-6): 74-78Crossref PubMed Google Scholar and TH2-mediated allergic diseases (see review9Ober C. Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery.Genes Immun. 2006; 7: 95-100Crossref PubMed Scopus (524) Google Scholar), and because other polymorphisms in IL4 have been associated with infection with other intracellular pathogens, including Plasmodium falciparum8Verra F. Luoni G. Calissano C. Troye-Blomberg M. Perlmann P. Perlmann H. et al.IL4-589C/T polymorphism and IgE levels in severe malaria.Acta Trop. 2004; 90: 205-209Crossref PubMed Scopus (31) Google Scholar and Leishmania chagasi. Although our sample size is small in terms of association studies, our results suggest that the asthma/atopy associated −590T allele is a marker for IL4 haplotypes that confer protection against T cruzi infection (positive serology). Further studies are warranted to clarify the relationship between genotype at this locus and the development of overt Chagas disease and subsequent clinical outcomes. Estimates of the coalescence time for a pair of sequences (haplotypes) were calculated by using T = D/2μl,E2Tang H. Siegmund D.O. Shen P. Oefner P.J. Feldman M.W. Frequentist estimation of coalescence times from nucleotide sequence data using a tree-based partition.Genetics. 2002; 161: 447-459PubMed Google Scholar where T is the time to the most recent common ancestor and D is the number of nucleotide differences between 2 sequences, μ is the mutation rate, and l is the length of the sequence in base pairs. We used 5 and 6 million years as the divergence time between human being and chimpanzee, which was considered the ancestral sequence, resulting in a range of estimates from 38,660 to 46,392 years ago, respectively. Using the highest (1.3 × 10−8) and lowest (2.5 × 10−8) mutation rate estimates from Nachman and Crowell,E3Nachman M.W. Crowell S.L. Estimate of the mutation rate per nucleotide in humans.Genetics. 2000; 156: 297-304Crossref PubMed Google Scholar divergence estimates range from 25,204 to 48,469 years ago. All 4 combinations of estimates were used to acquire a range of plausible coalescent times, placing the split before the spread of modern human beings into the new world.E4Fagundes N.J. Kanitz R. Eckert R. Valls A.C. Bogo M.R. Salzano F.M. et al.Mitochondrial population genomics supports a single pre-Clovis origin with a coastal route for the peopling of the Americas.Am J Hum Genet. 2008; 82: 583-592Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar, E5Goebel T. Waters M.R. O’Rourke D.H. The late Pleistocene dispersal of modern humans in the Americas.Science. 2008; 319: 1497-1502Crossref PubMed Scopus (581) Google Scholar, E6Kitchen A. Miyamoto M.M. Mulligan C.J. A three-stage colonization model for the peopling of the americas.PLoS ONE. 2008; 3: e1596Crossref PubMed Scopus (145) Google Scholar, E7Tamm E. Kivisild T. Reidla M. Metspalu M. Smith D.G. Mulligan C.J. et al.Beringian standstill and spread of Native American founders.PLoS ONE. 2007; 2: e829Crossref PubMed Scopus (429) Google Scholar It is likely, therefore, that genetic adaptations to T cruzi infection and Chagas disease occurred in the Bolivian indigenous populations before the influx of European genes during the past 500 years, approximately. Neighbor joining trees were constructed by using Network, again considering the chimpanzee as the outgroup. Network is used to infer phylogenetic networks and trees and to estimate dates. This program generates a graphic display of the full information content of sequence data such that each polymorphism distinguishing 2 haplotypes or haplotype groups is displayed. All possible shortest, least complex (ie, most parsimonious) trees are displayed in the output, as opposed to many tree-generating tools in which only the most likely result is displayed and all other options are ignored." @default.
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• W2164449595 title "Sequence variation in the IL4 gene and resistance to Trypanosoma cruzi infection in Bolivians" @default.
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